Investigating Nelistotug Advanced Solid Tumors: Study Rationale and CD96 Biology

Immune checkpoint inhibitors have fundamentally transformed clinical oncology over the past decade. However, primary and secondary therapeutic resistance continue to present substantial hurdles across diverse cancer types. To address these persistent challenges, clinical researchers are targeting novel inhibitory receptors to reinvigorate exhausted immune effector cells. Among these emerging targets, CD96 has gained significant attention as a key co-inhibitory checkpoint within the CD226 receptor axis. Consequently, evaluating nelistotug advanced solid tumors represents a vital milestone in next-generation cancer immunotherapy development. Nelistotug is a humanized monoclonal antibody engineered specifically to block CD96-mediated immunosuppression on T cells and natural killer cells. Preclinical evaluations demonstrated that CD96 inhibition enhances antitumor cytotoxic immunity, particularly when paired with programmed cell death protein 1 pathway blockade. Therefore, investigators initiated this first-in-human trial to evaluate nelistotug safety, pharmacokinetics, and preliminary therapeutic activity. By exploring monotherapy and rational combinatorial approaches, researchers sought to establish tolerability and identify clinical efficacy signals in heavily pretreated patient populations who have exhausted standard systemic options.

Clinical Trial Design and Patient Cohort Architecture

This first-time-in-human, multicenter, open-label Phase 1 trial evaluated nelistotug across distinct treatment arms in patients with recurrent or advanced solid tumors. Specifically, the study design incorporated three distinct cohorts to characterize dose escalation and clinical safety. Arm A evaluated nelistotug monotherapy administered intravenously every three weeks at escalating doses ranging from 2.1 mg to 1400 mg. Arm B investigated nelistotug at doses ranging between 70 mg and 1400 mg combined with fixed-dose dostarlimab at 500 mg every three weeks. Additionally, Arm F explored a triplet combination comprising nelistotug at 1400 mg, dostarlimab at 500 mg, and the anti-TIGIT monoclonal antibody belrestotug at 400 mg. In total, the trial enrolled 36 patients in Arm A, 33 patients in Arm B, and 3 patients in Arm F. Primary study endpoints were dose-limiting toxicities and the incidence of adverse events. Secondary endpoints assessed objective response rates, pharmacokinetics, and treatment immunogenicity, while exploratory endpoints evaluated disease control and CD96 receptor occupancy.

Safety Profile, Tolerability, and Dose Escalation Findings

Evaluating safety and identifying dose-limiting toxicities were the primary objectives of this early-phase oncology trial. Throughout dose escalation across all cohorts, investigators observed no dose-limiting toxicities in any participant. This favorable safety profile enabled successful escalation to the maximum planned nelistotug dose of 1400 mg in monotherapy and combination arms. Consequently, researchers established 1400 mg administered every three weeks as the recommended Phase 2 dose. Furthermore, no treatment-related fatal adverse events occurred during the study period. The observed adverse events were consistent with the expected safety profile of checkpoint inhibitor therapies. Most treatment-emergent toxicities were low grade and successfully managed with standard supportive protocols. Treatment discontinuations due to drug-related adverse events remained low across all cohorts. The triplet regimen in Arm F also showed manageable initial tolerability, although the sample size remained limited. Overall, nelistotug demonstrated an acceptable safety profile both as monotherapy and in combination with dostarlimab and belrestotug.

Pharmacokinetics and CD96 Receptor Occupancy Dynamics

Characterizing pharmacokinetic properties and target engagement is essential in early-phase biologic evaluations. In this Phase 1 trial, pharmacokinetic assessments showed predictable, dose-proportional increases in nelistotug exposure across all evaluated cohorts. Nelistotug exhibited favorable clearance kinetics without unexpected drug accumulation during repeated three-week treatment cycles. Importantly, pharmacodynamic evaluations demonstrated robust target engagement in peripheral blood immune cells. Nelistotug achieved greater than 95 percent CD96 receptor occupancy on circulating T cells and natural killer cells across evaluated dose ranges. Calculated serum concentrations confirmed that systemic exposures were sufficient to fully saturate the CD96 target within tumor tissue. Additionally, immunogenicity assessments revealed minimal anti-drug antibody formation, indicating a low risk of neutralizing responses. These pharmacodynamic observations confirm that the recommended Phase 2 dose of 1400 mg achieves continuous target saturation throughout the dosing interval. Thus, the trial successfully confirmed biological target engagement in human participants.

Antitumor Activity, Efficacy Signals, and Clinical Outlook

Although safety was the primary endpoint, the study rigorously evaluated antitumor efficacy across all patient cohorts. Overall, clinical responses were limited in this heavily pretreated patient population with advanced solid tumors. In Arm A, single-agent nelistotug did not produce objective radiological responses among the 36 enrolled patients. Similarly, the three patients enrolled in the exploratory triplet cohort of Arm F showed no objective responses. However, in Arm B, the combination of nelistotug and dostarlimab yielded measurable clinical activity. Among 33 evaluable participants in Arm B, one patient achieved a complete response and another achieved a partial response, representing an objective response rate of six percent. These clinical findings indicate that while CD96 monotherapy offers limited activity in refractory disease, combinatorial strategies warrant further investigation. Future clinical research must focus on identifying predictive biomarkers and testing CD96 inhibitors in earlier disease lines or alongside synergistic immunotherapies to maximize therapeutic potential.

Frequently Asked Questions

What is nelistotug and what is its mechanism of action in oncology?

Nelistotug is an investigational humanized monoclonal antibody designed to selectively target and inhibit CD96, a co-inhibitory checkpoint receptor expressed on T cells and natural killer cells. By blocking CD96 signaling, nelistotug prevents immunosuppressive interactions, thereby promoting cytotoxic antineoplastic immune responses against tumor cells. It has been evaluated both as monotherapy and in combination with other immune checkpoint inhibitors like dostarlimab and belrestotug.

What was the recommended Phase 2 dose established for nelistotug?

The recommended Phase 2 dose for nelistotug was established at 1400 mg administered intravenously every three weeks. This dose level was selected because it demonstrated acceptable safety with no dose-limiting toxicities during dose escalation. Furthermore, pharmacodynamic evaluations confirmed that 1400 mg achieved greater than 95 percent CD96 receptor occupancy in peripheral immune cells, ensuring complete target saturation within tumor tissues.

What antitumor efficacy did nelistotug demonstrate in this Phase 1 trial?

Nelistotug monotherapy and triplet therapy showed no objective radiological responses in heavily pretreated advanced solid tumors. However, combining nelistotug with the anti-PD-1 antibody dostarlimab produced an objective response rate of six percent, comprising one complete response and one partial response. These findings indicate that while single-agent efficacy is limited, rational combinatorial strategies and predictive biomarker enrichment remain essential for future development.

Disclaimer: This content is for informational and educational purposes only, intended for healthcare professionals. It does not constitute medical advice or establish a doctor-patient relationship. Clinical decisions should rely on individualized patient assessment, multidisciplinary consultation, and diagnostic evaluations. Refer to the latest local and national guidelines for clinical practice.

References

1. Siu LL et al. A Phase 1 First-Time-in-Human, Open-Label Study of Nelistotug Administered to Patients with Advanced Solid Tumors. Clin Cancer Res. 2026 Aug 27. doi: 10.1158/1078-0432.CCR-25-4374. PMID: 42658188.


2. Spigel DR et al. Phase 2 study of belrestotug plus dostarlimab in patients with previously untreated, advanced/metastatic non-small cell lung cancer: GALAXIES Lung-201. ESMO Congress 2024.


3. Dougall WC et al. TIGIT and CD96: new checkpoint targets for cancer immunotherapy. Immunol Rev. 2017;276(1):112-120.